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Identifying potential binding sites of Nectin 4 for bespoke anti-cancer peptides

Stanton, Emma (2021) Identifying potential binding sites of Nectin 4 for bespoke anti-cancer peptides. Masters thesis, University of Essex.

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Abstract

Nectin 4 is a cell adhesion protein found between epithelial and endothelial cells during embryogenesis; expression then falls to low levels during adulthood. However, Nectin 4 has also been shown to be over expressed in some of the deadliest/common cancer types of the bladder, pancreas, lung and breast. Nectin 4 has also been reported to play a role in metastasis. Consequently, lending itself to be an attractive drug target for anti-cancer treatment. Bicycle therapeutics has taken advantage of this to design novel Bicycle drug conjugates (BDCs) to target the ectodomain of Nectin 4, present on the surface of cancer cells. Bicycle peptides are small bespoke synthetic cyclic peptides conjugated to an MMAE (Monomethyl auristatin E) toxin, which have significantly reduced toxicity issues compared to those typically associated with conventional antibody drug conjugates. This is due to their unique design, size and excretion pathway. The precise binding sites of bicycle peptides to Nectin 4 are currently unknown. The initial aim of this project was to produce Nectin 4 constructs, conduct co-crystallisation with BDCs and perform x-ray crystallography studies, to elucidate the bicycle binding sites and the entire crystal structure of the ectodomain. However, due to the COVID 19 pandemic this work was interrupted leading to an in silico alternative approach being sourced. Potential binding sites were identified using molecular dynamics simulations and a protein surface pocket identifier, EPOS_BP. Six out of a total of 14 pockets were chosen for binding analysis based on durability features. All pockets are hydrophilic, favouring electrostatic interactions and so compatible with hydrophilic bicycle peptides. Structures containing the open pockets will be used in future experimental docking with bicycle peptides to reveal where bicycle peptides bind to D1 domain of Nectin The results of which will provide a rational behind bicycle binding and aid further optimisation of bicycle binding.

Item Type: Thesis (Masters)
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Jim Jamieson
Date Deposited: 28 Jun 2021 08:39
Last Modified: 28 Jun 2021 08:39
URI: http://repository.essex.ac.uk/id/eprint/30665

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